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WO1994008589A1 - Traitement du lupus erythemateux systemique a la deshydroepiandrosterone - Google Patents

Traitement du lupus erythemateux systemique a la deshydroepiandrosterone Download PDF

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Publication number
WO1994008589A1
WO1994008589A1 PCT/US1993/009621 US9309621W WO9408589A1 WO 1994008589 A1 WO1994008589 A1 WO 1994008589A1 US 9309621 W US9309621 W US 9309621W WO 9408589 A1 WO9408589 A1 WO 9408589A1
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WIPO (PCT)
Prior art keywords
dhea
patients
day
patient
treatment
Prior art date
Application number
PCT/US1993/009621
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English (en)
Inventor
James L. Mcguire
Ronald F. Van Vollenhoven
Edgar G. Engleman
Original Assignee
The Board Of Trustees Of The Leland Stanford Junior University
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Filing date
Publication date
Application filed by The Board Of Trustees Of The Leland Stanford Junior University filed Critical The Board Of Trustees Of The Leland Stanford Junior University
Publication of WO1994008589A1 publication Critical patent/WO1994008589A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the field of this invention concerns the treatment of systemic lupus erythematosus.
  • SLE Systemic lupus erythematosus
  • Clinical manifestations of systemic lupus erythematosus include, but are not limited to, the following: Systemic — fatigue, malaise, fever, nausea, weight loss; Musculoskeletal — arthralgias/myalgias, non-erosive pc yarthritis, yopathy/myositis, ischemic necrosis of bo ⁇ .e; Cutaneous — malar rash, oral ulcers, rashes, alopecia, vasculitis; Hematologic — anemia, leukopenia, lymphopenia, splenomegaly, lymphadenopathy; Neurologic — seizures, peripheral neuropathy; Cardiopulmonary pleurisy, myocarditis, lupus pneumonitis, interstitial fibrosis; Renal — proteinuria (>500 mg/24 hrs.), nephrotic syndrome, renal failure; Gastrointestinal — ascites, abnormal liver enzymes; Thrombosis; Fe
  • DHEA Dehydroepiandrosterone
  • a natural androgen that is an intermediate in the synthetic pathway of cholesterol to testosterone and it is the most abundant secretory product of human adrenal glands (Vande Wiele, et al . Recent Prog . Horm . Res . (1963), 19, 275).
  • DHEA has only mild intrinsic androgenic activity (Parker, LN, Endocrin. Metab. Clin. N. AM., Vol. 20, pgs.401-421 (1991)).
  • About 30 mg/day of DHEA is produced by the adrenal glands in the form of the inactive sulfate ester and DHEA serum levels show a striking age-related decline (Barrett-Connor, et al . New Engl . J. Med . (1986), 315, 1519) .
  • DHEA oxidized glutathione
  • metabolites or derivative thereof (such as DHEA-sulfate) is administered to lupus erythematosus patients at a level to enhance the normal blood level by at least about 10%.
  • One or more doses may be administered daily to maintain the desired concentration, where the DHEA may be administered in conjunction with other drugs conventionally used for the treatment of lupus erythematosus.
  • the treatment may be continuous, intermittent, or associated with episodic events.
  • One advantage of the present invention is that the use of DHEA in the treatment of lupus erythematosus allows the reduction of therapeutic levels of corticosteroids.
  • One embodiment of the invention includes a pharmaceutical formulation comprising dehydroepiandro- sterone or its sulfate ester and a second drug selected from the group consisting of a non-steroidal anti-inflammatory drug, a glucocorticosteroid and an antimalarial drug.
  • This formulation is prepared at a therapeutic dosage for the treatment of lupus erythematosus.
  • Figure 1 presents SLE-DAI scores (range 1-105) determined on the basis of clinical and laboratory criteria, for ten patients who completed three months of DHEA treatment, and eight who continued for an additional three months. The figure also includes physician and patient overall numerical assessments (1-100) of the treatment.
  • DHEA dehydroepiandrosterone
  • a therapy comprising dehydroepiandrosterone (DHEA) or a derivative thereof, optionally in combination with other drug regimens employed for the treatment of lupus erythematosus.
  • DHEA or the metabolite DHEA sulfate will be employed, individually or in combination, where the sulfate will be present as a physiologically-acceptable salt.
  • the DHEA may be administered in a variety of ways, orally, parenterally, or inhalation.
  • the DHEA may be injected subcutaneously, intraperitoneall , intravascularly, etc .
  • the DHEA may be formulated in a variety of ways.
  • the proportion of therapeutically active to carrier substance may vary from about 0.5-100 wt.%.
  • the compositions can be prepared in various pharmaceutical forms, such as granules, tablets, pills, suppositories, capsules, suspensions, salves, lotions and the like.
  • compositions containing the therapeutically-active compounds can be used to make up compositions containing the therapeutically-active compounds.
  • Diluents known to the art include vegetable and animal oils and fats. Stabilizing agents, wetting and emulsifying agents, salts for varying the osmotic pressure or buffers for securing an adequate pH value, and skin penetration enhancers can be used as auxiliary agents.
  • the pharmaceutical composition will generally contain from about 5-100% by weight of the active material.
  • the composition will generally have from about 0.5-50 wt.% of the active material.
  • Various carriers include excipients, tocopherol, dimethyl sulfoxide, etc .
  • compositions will generally be administered daily, in an amount to provide at least about a 10%, usually at least about 25%, increase in the blood level of DHEA.
  • the total daily dosage will be at least about 10 mg, usually at least about 25 mg, preferably about 50 mg to 250 mg, and not more than about 500 mg.
  • the amount being administered may vary with the general health of the patient, the response of the patient to the drug, whether the DHEA is used by itself or in combination with other drugs, and the like. Daily administrations may be one or more times, usually not more than about four times, particularly depending upon the level of drug which is administered.
  • drugs which may be used in accordance with conventional treatments include non-steroidal anti-inflammatory drugs, antimalarials, glucocortico- steroids, etc . These drugs include hydroxychloroquine, prednisone, quinacrine, azathioprine, etc . Dosage for prednisone will generally be from about 1-15, more usually from about 1-12 mg/day.
  • the additional drugs may be administered separately or in conjunction with DHEA and may be formulated in the same formulation with DHEA. Experiments performed in support of the present invention demonstrate the usefulness and efficacy of treating lupus erythematosus with DHEA and DHEA derivatives, such as DHEA-sulfate.
  • Proteinuria is considered to be pathological when the protein content of urine is above 150 mg/day; urine protein concentrations of >350 mg/day are considered to be massive proteinuria. Persistent proteinuria at such levels tends to lead to nephrotic syndrome and is suggestive of glomeruli destruction.
  • DHEA or DHEA derivatives appear to assist in the management of proteinuria in patients afflicted with lupus erythematosus.
  • initial proteinuria levels ranged from 1700 to 8640 mg/day. After six months of treatment this had decreased to 430 mg/day.
  • proteinuria had been documented over 12 months prior to the study, with daily protein excretion ranging from 1 to 8 gm/day. After 3 months of treatment protein secretion was at 375 mg/day, and after 6 months at 243 mg/day.
  • Examples 1 and 2 show that DHEA was generally well tolerated by the patients under treatment.
  • the use of DHEA coincided with subjective and objective improvement in the clinical status of most patients.
  • corticosteroid requirements decreased in most patients over the 3-6 month treatment period. From the patients' perspective, 8 of 10 felt the medication was helping them.
  • EXAMPLE 1 Eight Patient Study Eight female pre-menopausal SLE patients with mild to moderate disease were given DHEA 200 mg/day, open label for 3 months, while allowing changes in other medications to be made as clinically indicated. After 3 months, the SLE-disease activity index score (SLE-DAI) had improved by a clinically-significant margin in 5 patients, was unchanged in 2, and had worsened in 1 patient. Of 5 patients who were on prednisone at onset, 3 were able to significantly reduce the dose during the trial (average daily dose of the 5 patients on prednisone: 19.0 mg at onset vs. 13.6 mg after 3 months on DHEA).
  • SLE-DAI SLE-disease activity index score
  • Table 1 The following tables provide the patient profiles (Table 1) , a summary of the outcome measures (Table 2) , the tolerance and side effects (Table 3) , and medication profiles (Table 4) .
  • SLE-DAI was scored as improved/worsened if the change was 10% or greater.
  • Patient OA was scored as improved/worsened if the change was 20% or greater.
  • ESR was scored as improved/worsened only if values were outside the normal range, and cha 10 was 20% or greater.
  • Corticosteroid dose was scored as improved/worsened if the change was 20% or greater.
  • the dose was reduced in 7 and unchanged in 1 (average dose 12.4 mg/day 10 prednisone or equivalent) .
  • Renal disease was present in three patients, consisting of stable proteinuria without abnormalities in the urine sediment and without changes in serum creatinine or creatinine clearance. No overt CNS lupus was present in any of the patients, although mild, subjective cognitive impairment was noted by some, and "lupus headaches" were noted in four.
  • DHEA and DHEA-sulfate powders were obtained from the Sigma Chemical Co. (St. Louis, MO) , capsules of which were prepared by the Stanford University Hospital pharmacy.
  • the patients were followed at monthly intervals by the rheumatologist carrying the primary responsibility for the patient as well as one of the investigators. Throughout the study period, patients were treated based on clinical status, per the discretion of the physician carrying the primary responsibility for the patient. Changes in medications were allowed, including changes in dosages or the addition of new medications.
  • SLE-DAI SLE-disease activity index
  • DHEA and DHEA-sulfate (D-S) were determined at monthly intervals. A slow, steady rise of D-S levels over the course of 1-2 months was seen, reaching a plateau at 439-1,659 ⁇ g/dl. Levels of DHEA showed similar increases, but were more variable, in keeping with the known marked circadian variation of this hormone (Parker, LN, Control of adrenal androgen secretion, Endocrin Metab Clin. N. AM., Vol. 20:pgs.401- 421, (1991)).
  • Serum testosterone levels increased in tandem with D- S and DHEA. Baseline levels of DHEA and D-S were typically low in these patients and steady state levels were obtained slowly.
  • SLE-DAI score was determined on the basis of clinical and laboratory criteria as referenced, (Bombardier, C. , Derivation of the SLE-DAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE, Arthritis Rheum., Vol. 35; pgs. 630-640, (1992). Physicians were asked for overall assessments on a visual analog scale. A summary of these outcome measures after 3 months of treatment is given in Table 6: values given are mean ⁇ standard error. P values given are for paired two-sided Student t-test.
  • prednisone (20 mg daily) had not appreciably changed the level of proteinuria. Moreover, a month long attempt at improving the proteinuria with prednisone 60 mg/day was similarly unsuccessful. When DHEA treatment was initiated, a 24- hour collection of urine showed 4000 mg/day protein. After six months of treatment this had decreased to 430 mg/day.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On traite le lupus érythémateux systémique (LES) à la déshydroépiandrostérone ou son métabolite, l'ester de sulfate, en association ou non à d'autres thérapies. On observe pendant le traitement une amélioration sensible des patients souffrant de LES.
PCT/US1993/009621 1992-10-09 1993-10-08 Traitement du lupus erythemateux systemique a la deshydroepiandrosterone WO1994008589A1 (fr)

Applications Claiming Priority (2)

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US958,911 1978-11-08
US95891192A 1992-10-09 1992-10-09

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003993A3 (fr) * 1994-08-05 1996-06-20 Univ Rockefeller Modulation de l'activite fonctionnelle de thymocytes et de lymphocytes t
DE19618778A1 (de) * 1995-05-12 1997-01-23 Stefan Dr Schulz Verwendung von Dehydroepiandrosteron und Derivaten hiervon
WO1998047516A1 (fr) * 1997-04-17 1998-10-29 Prendergast Patrick T Therapie combinee mettant en application des 17-cetosteroides et des inhibiteurs d'interleukine, ou interleukine-10 eventuellement avec des inhibiteurs d'interleukine
WO1999025333A1 (fr) * 1997-11-19 1999-05-27 Humanetics Corporation UTILISATION DE Δ5-ANDROSTENE-3β-OL-7,17-DIONE DANS LE TRAITEMENT DU LUPUS ERYTHEMATEUX
WO2001035949A3 (fr) * 1999-11-12 2002-05-02 Genelabs Tech Inc Traitement du lupus erythemateux dissemine avec la dehydroepiandrosterone
WO2006036484A3 (fr) * 2004-09-24 2006-06-01 Rxdino Llc Traitement de dermatite au moyen de combinaisons de deshydroepiandrosterone-glucocorticoide
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994008589A1 (fr) * 1992-10-09 1994-04-28 The Board Of Trustees Of The Leland Stanford Junior University Traitement du lupus erythemateux systemique a la deshydroepiandrosterone
US6667299B1 (en) * 2000-03-16 2003-12-23 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
CN101543500A (zh) 1999-03-18 2009-09-30 基因实验室技术公司 Dhea制剂及方法
US6605591B1 (en) 1999-11-12 2003-08-12 Genelabs Technologies, Inc. Treatment of subnormal bone mineral density
US20060178354A1 (en) * 2003-02-27 2006-08-10 Lucas John M Methods and compositions for the treatment of chronic pain using dhea and derivatives thereof
DK1615626T3 (da) * 2003-04-24 2010-02-08 Jagotec Ag Tablet med farvet kerne
AU2004231362B2 (en) 2003-04-24 2009-11-12 Jagotec Ag Delayed release tablet with defined core geometry
DE102004043863A1 (de) * 2004-09-10 2006-03-16 Nitec Pharma Ag Tabletten mit orts- und zeitgesteuerter Wirkstofffreisetzung im Gastrointestinum
EA015304B1 (ru) 2006-08-03 2011-06-30 Нитек Фарма Аг Лечение ревматоидного заболевания глюкокортикоидами с отсроченным высвобождением
WO2008021256A2 (fr) * 2006-08-11 2008-02-21 Aqua Resources Corporation Hydroxydes métalliques nanoplaquettaires et leurs méthodes d'élaboration

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US4628052A (en) * 1985-05-28 1986-12-09 Peat Raymond F Pharmaceutical compositions containing dehydroepiandrosterone and other anesthetic steroids in the treatment of arthritis and other joint disabilities
US5001119A (en) * 1987-11-25 1991-03-19 Schwartz Arthur G 16-substituted androstanes and 16-substituted androstenes
WO1994008589A1 (fr) * 1992-10-09 1994-04-28 The Board Of Trustees Of The Leland Stanford Junior University Traitement du lupus erythemateux systemique a la deshydroepiandrosterone

Non-Patent Citations (7)

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COTTRAM,G.L. ET AL: "ALTERED LIPID METABOLISM AND INDUCTION OF PEROXISOMAL ACTIVITY IN NZB/W MICE FED A DIET CONTAINING 0.45% DEHYDROEPIANDROSTERONE (DHA).", THE JOURNAL OF CELL BIOLOGY, vol. 107, no. 6PT3, 1988, pages 122A *
LUCAS, J.A. ET AL: "PREVENTION OF AUTOANTIBODY FORMATION AND PROLONGED SURVIVAL IN NEW ZEALAND BLACK/NEW ZEALAND WHITE F1 MICE FED DEHYDROEPIANDROSTERONE", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 75, no. 6, June 1985 (1985-06-01), pages 2091 - 2093 *
MATSUNAGA, A. ET AL: "EFFECTS OF DEHYDROEPIANDROSTERONE (DHA) ADMINISTRATION ON MACROPHAGE FUNCTION AND SPLEEN CELL MITOGENIC RESPONSE IN NZB/W FEMALE MICE.", THE FASEB JOURNAL, vol. 2, no. 5, 20 March 1988 (1988-03-20), pages A1048 *
MATSUNAGA, AKIRA ET AL: "DEHYDROEPIANDROSTERONE PREVENTION OF AUTOIMMUNE DISEASE IN NZB/W F1 MICE: LACK OF AN EFFECT ON ASSOCIATED IMMUNOLOGICAL ABNORMALITIES", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 992, no. 3, 15 September 1989 (1989-09-15), pages 265 - 271 *
VAN VOLLENHOVEN, R.F. ET AL: "TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS WITH DEHYDROEPIANDROSTERONE, A PILOT STUDY", ARTHRITIS AND RHEUMATISM, vol. 35, no. 9, September 1992 (1992-09-01), pages S55 *
VAN VOLLENHOVEN, R.F. ET AL: "TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS WITH DEHYDROEPIANDROSTERONE. FOLLOW-UP FROM AN OPEN LABEL CLINICAL TRIAL", ARTHRITIS AND RHEUMATISM, vol. 36, no. 9, 1993, pages S228 *
VAN VOLLENHOVEN, R.F. ET AL: "TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS WITH DEHYDROEPIANDROSTERONE. INTERIM ANALYSIS OF A DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED, CLINICAL TRIAL", ARTHRITIS AND RHEUMATISM, vol. 36, no. 9, 1993, pages S92 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996003993A3 (fr) * 1994-08-05 1996-06-20 Univ Rockefeller Modulation de l'activite fonctionnelle de thymocytes et de lymphocytes t
DE19618778A1 (de) * 1995-05-12 1997-01-23 Stefan Dr Schulz Verwendung von Dehydroepiandrosteron und Derivaten hiervon
WO1998047516A1 (fr) * 1997-04-17 1998-10-29 Prendergast Patrick T Therapie combinee mettant en application des 17-cetosteroides et des inhibiteurs d'interleukine, ou interleukine-10 eventuellement avec des inhibiteurs d'interleukine
WO1999025333A1 (fr) * 1997-11-19 1999-05-27 Humanetics Corporation UTILISATION DE Δ5-ANDROSTENE-3β-OL-7,17-DIONE DANS LE TRAITEMENT DU LUPUS ERYTHEMATEUX
US6593316B2 (en) 1997-11-19 2003-07-15 Henry A. Lardy Use of Δ5-androstene-3βol-7,17-dione in the treatment of lupus erythematosus
US6924274B2 (en) 1997-11-19 2005-08-02 Humanetic Corp. Use of Δ5-androstene-3β-ol-7,17-dione in the treatment of lupus erythematosus
WO2001035949A3 (fr) * 1999-11-12 2002-05-02 Genelabs Tech Inc Traitement du lupus erythemateux dissemine avec la dehydroepiandrosterone
US6552010B1 (en) 1999-11-12 2003-04-22 Genelabs Technologies, Inc. Treatment of SLE with dehydroepiandrosterone
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2006036484A3 (fr) * 2004-09-24 2006-06-01 Rxdino Llc Traitement de dermatite au moyen de combinaisons de deshydroepiandrosterone-glucocorticoide

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US5567696A (en) 1996-10-22
US5817650A (en) 1998-10-06

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